BIO-BUZZInhibition of Angiogenesis with Bevacizumab Shows Promise in the
Treatment of Recurrent or Advanced Non–Small-Cell Lung CancerT
his year in the US, the American Cancer Society estimates that lung cancer will kill more people than breast, prostate, colon, liver, and kidney cancers combined, making it the leading cause of cancer death among Americans.1
There will be more than 213,000 new cases of lung cancer diagnosed in 2007, and lung cancer will account for about 15% of all new cancers.1
Because most lung cancers are diagnosed late in the course of the disease, only about 15% of patients survive 5 years or more.2
Investigations comparing various platinum-based regimens failed to produce a significant impact in the outcomes for patients with non-small cell lung cancer (NSCLC),3,4
and this therapeutic modality may be reaching a plateau. Therapeutic advances will likely require the addition of agents with a different mechanism of action.Overview of Bevacizumab
Bevacizumab (Avastin®, Genentech/Roche) is a recombinant humanized antibody to vascular endothelial growth factor (VEGF), a protein that plays a critical role in tumor angiogenesis. It was formerly known as anti-VGEF. Bevacizumab binds VEGF and prevents the interaction of VEGF with its receptors (Flt-1 and KDR) on the surface of endothelial cells.5
The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis.6
Treatment with bevacizumab has been shown to benefit patients with a variety of cancers. It is the first US Food and Drug Administration (FDA)–approved therapy designed to inhibit angiogenesis, and is currently approved, in combination with intravenous 5-fluorouracil–based chemotherapy, for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum, and in combination with carboplatin and paclitaxel for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic nonsquamous NSCLC.ECOG Study E4599
Recently, the results of a large-scale, multicenter, randomized, open-label, Eastern Cooperative Oncology Group (ECOG) trial (ECOG Study E4599) evaluating bevacizumab for the treatment of recurrent or advanced non-small-cell lung cancer were reported.7
In this trial, 878 patients with recurrent or advanced non-small-cell lung cancer (Stage IIIB or IV) were assigned to chemotherapy with paclitaxel and carboplatin alone (n=444) or paclitaxel and carboplatin plus bevacizumab (n=434). Chemotherapy was administered every 3 weeks for 6 cycles, and bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable. Patients with squamous-cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or performance status (ECOG performance status, >1) were excluded. The primary end point was overall survival.
The median survival was 12.3 months in patients treated with chemotherapy plus bevacizumab, compared with 10.3 months in those treated with chemotherapy alone (P
= 0.003). The median progression-free survival in the two groups was 6.2 and 4.5 months, respectively (P
< 0.001), with corresponding response rates of 35% and 15% (P
The rates of the following severe (Grade 3-5 for nonhematologic and Grade 4-5 for hematologic) adverse events were significantly greater in patients receiving bevacizumab plus chemotherapy compared to those receiving chemotherapy alone: hypertension, proteinuria, bleeding, neutropenia, febrile neutropenia, thrombocytopenia, hyponatremia, rash, and headache. Neutropenia occurred in 26% of patients treated with bevacizumab plus chemotherapy and 17% of those who received chemotherapy alone.
The rate of hemoptysis requiring medical intervention among patients treated with bevacizumab plus chemotherapy arm was 1.9%, compared to 0.2% among those treated with chemotherapy alone. There were 15 deaths related to the adverse treatment effects in patients treated with bevacizumab plus chemotherapy, of which 5 were due to pulmonary hemorrhage, 5 were due to complications of febrile neutropenia, and the remainder were due to other sites of hemorrhage and a probable pulmonary embolism. Among patients treated with chemotherapy alone, two deaths related to the adverse effects of treatment occurred, of which one was from gastrointestinal hemorrhage and one from febrile neutropenia.